African trypanosomes are the causative agents of human sleeping sickness as well as fatal disease in other animals. Biological variation among genetically related African trypanosomes is the central theme of this proposal, with the primary focus on virulence. The hypothesis addressed is that African trypanosomes regulate the clonal expression of virulence during infection of a mammalian host by differential expression of specific genes. The experimental foundation for the proposed studies includes a well characterized and clinically relevant Trypanosoma brucei rhodesiense model system of virulence, and a panel of differentially expressed genes cloned from high and low virulence trypanosomes. In this proposal, candidate virulence-associated genes will be selected and tested for functional and genetic linkages to specific virulence phenotypes. The results will provide new and relevant information on trypanosome cell biology and mechanisms of pathogenesis that may lead to new avenues for treatment or control of trypanosomiasis.